Abstract 3797: Anti-cancer effects of novel imipridone DRD2 antagonists in a panel of human cancer cell lines

Abstract

Abstract Purpose: The dopamine D2-like receptors (DRD2) belong to the family of G-protein coupled receptors, which play crucial roles in various neurophysiological processes and in tumorigenesis. Several reports have described the role of DRD2 in cancer progression by influencing cellular invasion, migration, apoptosis and proliferation. Thereby, the pharmacological targeting of the DRD2 may serve as a potential therapeutic approach for cancer treatment. The imipridones ONC201 and ONC206 (Oncoceutics) are selective small molecule antagonists of DRD2 that inhibit Akt/Erk signaling pathway, and thus serve as promising anti-cancer agents for many tumors. Methods and Results: A MTT ([3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide]) cell growth assay was used to measure the in vitro anti-proliferative effects of ONC201 and ONC206 on different types of human cancer cells, namely HCT116 (colon), MCF7 (breast), UC6 (bladder), PC3 and DU145 (prostate). Cells were seeded 24 hours (h) before drug treatment, and then treated with either ONC201 or ONC206 at different concentrations ranging from 1 to 100 µM. Cell proliferation was measured at 24, 48 and 72 h post drug treatment. Our results show that both ONC201 and ONC206 had considerable, dose-dependent anti-proliferative effects on all the tested cell lines after three consecutive days of treatment. Furthermore, we assessed the effects of the two drugs on nervous system tumors, namely neuroblastoma (NB) and medulloblastoma (MB). Pediatric human NB cell lines (MYCN-amplified IMR-32 and the non MYCN-amplified SKNSH) exhibited a dose-dependent inhibition on cellular proliferation and increased apoptosis at 48 and 72 h after drug treatment. ONC206 was more potent than ONC201 at inhibiting cell proliferation in both cell lines. Cell migration was also inhibited with both drugs in the IMR-32 and SKNSH NB cell lines. Cell viability was assessed in human MB D556 and D283 cell lines, which was reduced at 48 and 74 h post treatment with both ONC201 and ONC206 compared to vehicle treated cells. Tumor-sphere formation efficiency was inhibited in a dose-dependent manner in both human NB (IMR-32 and SKNSH) and MB (D556 and D283) cells after treatment with either drug. Western blot analysis revealed differential protein expression of stem cell maintenance and tumorigenic proteins, including OCT-4, MYCN, L1-CAM, HSP90, FABP5, VEGFR2 and RAB5C after treatment with either ONC201 or ONC206. Conclusion: Our data show potent anti-stem cell maintenance as well as anti-proliferative, anti-migratory, anti-viability and pro-apoptotic activity of both ONC201 and ONC206 on cancer cell lines, with ONC206 showing greater potency than ONC201. Our future directions include utilizing a combinatorial multi-modality therapy to treat a panel of pediatric and adult neurological tumors with ONC 201/206 and other selective inhibitors of tumorigenic pathways to completely eliminate the highly resistant sub-population of cancer stem cells, and delay malignant recurrence. Citation Format: Reine Hanna, Reem Daouk, Farah Ballout, Sarra El-Soussie, Jad Abdallah, Wassim Abou-Kheir, Tamara Mary Abou-Antoun. Anti-cancer effects of novel imipridone DRD2 antagonists in a panel of human cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3797.